Emulsion of pilocarpine for ophthalmic use

ABSTRACT

An easy to apply, stable and effective form of pilocarpine is provided by an oil-in-water emulsion of pilocarpine.

United States Patent inventors Russell E. Phares, .Ir.;

Hans H. Kaspar, both of Sunnyvale, Calif. 745,175

July 16, 1968 Sept. 21, 1971 Barnes-Hind Pharmaceuticals, Inc.

Appl. No. Filed Patented Assignee EMULSION OF PILOCARPINE FOR OPHTHALMICUSE [56] References Cited UNITED STATES PATENTS 3,450,814 6/1969Bechtoid et al 424/273 OTHER REFERENCES Chem. Abstracts, Vol. 63, [965p. 2856g. Remington, Remingtons Pharmaceutical Sciences, l3th Ed. 1965p. 884,979.

Primary ExamirierStanley J. Friedman Assistant ExaminerVincent D. TurnerAttorney-Eckhoff and Hoppe ABSTRACT: An easy to apply, stable andeffective form of pilocarpine is provided by an oil-in-water emulsion ofpilocarpine.

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ATTORN EYS EMULSION OF PILOCARPINE FOR OPHTHALMIC USE SUMMARY OF THEINVENTION Pilocarpine is used as an antiglaucoma agent over long periodsof time. Generally the condition is such that it must be used for therest of the patients life. Since many of the users are old and infirm,they find great difficulty instilling medicine into the eye. The easiestform of application of this medicine is a liquid drop while the mosteffective form of medication previously known is an ointment ofsemisolid material. The ointment is more effective both from the depthand duration of clinically significant response. However, many patientshave difficulty in applying an ointment and it also obscures the visionfor prolonged period of time. It is also difficult for the patient tojudge when he has instilled an effective amount of either the aqueousdrop or the solid ointment in his eye since a drop may catch just thecomer of the eye and be rinsed out by tear fluid while the ointment canobscure vision even though it is applied only to the eyelid and theeyelashes. For these reasons, ophthalmologists normally restrict the useof ointment to bedtime, if at all, despite the advantage of lessfrequent instillation and better effect.

In accordance with the present invention, a fluid emulsion is providedwhich combines the ease of administration of aqueous drops with thedepth and duration of an ointment. With the emulsion of the presentinvention there is a brief obscuring of vision but this brief obscuringis actually an advantage because the patient can then judge whether hehas instilled an effective amount of the medication on the surface ofthe eye itself.

It is surprising that the effectiveness of pilocarpine in theformulation of the present invention is virtually the same as theointment since the pilocarpine is contained exclusively in the aqueousphase of the emulsion. Although the invention is not based on any theoryof its operation, it is believed that this unexpected result comes fromthe effect of immobilizing the aqueous phase by the oil droplets,thereby permitting longer contact of the pilocarpine with the surface ofthe eye before it is normally drained.

Another advantage of the present invention is that the chemicaldecomposition of pilocarpine is retarded when in the emulsion of thepresent invention so that it can be formulated and have a substantialshelf life.

Further advantage of the present invention is that the emulsion can beproduced in sterile form while ointments are not available as sterileproducts because of processing difficulties.

BRIEF DESCRIPTION OF THE DRAWINGS DESCRIPTION OF THE PREFERREDEMBODIMENTS In its simplest form the formulation of the presentinvention includes pilocarpine, water, a physiologically acceptable oiland a physiologically acceptable emulsifying agent. Other materials areadvantageously added to adjust the pH, to act as buffering agents and torender the emulsion isotonic. Fungicidal and sterilizing agents as wellas a chelating agent may also be employed. 7

The formulation of the present invention contains from 0.25

to 8 percent pilocarpine and from 10 to 80 percent of oil. The.

balance of the formulation is water plus any of the minor ingredientsmentioned above. Nonnally the pH is adjusted in the range of 4.5'to 7and preferably is about 6.

Pilocarpine can be employed as the base material itself or its saltssuch as pilocarpine hydrochloride, pilocarpine borate or pilocarpinenitrate can be employed. Preferably the salts are employed because oftheir greater stability.

Various oils can be used such as mineral oil, U.S.P., silicone oils orvegetable oils such as corn oil, peanut oil, olive oil or the like.Preferably mineral oil is employed because of its acceptance by themedical profession, superior stability and low cost.

In preparing the formulations of the present invention, the emulsifyingagent or agents are added to the oil and the mixture is then heated toabout 60 C. This warm mixture is added with rapid stirring to waterwhich also is about 60 C. and which contains the pilocarpine as well asany of the minor ingredients mentioned above. The resulting oil-in-wateremu'lsion is then allowed to cool slowly to room temperature while it isslowly stirred. The formulation is then ready for use.

A large number of emulsifying agents are suitable for use with thepresent invention. The requirements are that the material formoil-in-water emulsions and that it be nontoxic in the concentrationemployed. Thus suitable materials include carbohydrates such as acacia,gum tragacanth and methylcellulose; alcohols and esters of alcohol suchas lecithin and cholesterol and its esters; polyoxyethylene derivativessuch as polyoxyethylene (40 units) sterate, polyoxyethylene cetyl ether,ethylene oxide reaction product of wool fat, and polyethylene oxidesorbitan reaction product of wool fat as well as sorbitan and sorbidederivatives such as sorbitan trioleate and polyoxyethylene (20) sorbitantrioleate.

As been mentioned above, various additional materials can be added.These include sodium acid phosphate, disodium acid phosphate asbuffering agents, benzalkonium chloride as a fungicide and sterilizingagent, chelating such as sodium ethylene diamine tetra-acetic acid andsalts such as sodium chloride or sodium nitrate to render the emulsionisotonic.

Pilocarpine and its salts, like many drugs, are chemically unstable inaqueous solution and will therefore lose potency with time. The loss ofpilocarpine nitrate from a conventional solution and the product of thepresent invention when both samples were stored under identicalaccelerated conditions, is shown in FIG. 1. As can be seen, a higherconcentration of the therapeutically effective form of the drug isalways present in the emulsion than is in an equivalent conventionaldosage from. At the end of 30 days the emulsion has 88 active drug ascompared to 79.5 percent in the aqueous solution. These results aresince in both samples, of the drug was contained in the water.

An accepted method of comparing the biological availability of a drugfrom various dosage forms is to compare the areas under their biologicaland neither the disadvantages solution and human efficacy formulationsof response versus time plots. Applying this method to the data in FIGS.2 and 3, it is found that the emulsion of the present invention has morethan twice the biological availability or activity of an equivalentconventional dosage form. The release or availability of the drug fromthe emulsion is as good as from an ointment but the emulsion has theadvantages of a solution and neither the disadvantages of a solution oran ointment. The availability results shown in FIGS. 2 and 3 aresurprising in view of the fact that the drug is present in the water inboth dosage forms. Assay has shown that none of the drug in the emulsionis present in the oil phase of the preparation. Although this particularwork was done with rabbits, pilocarpine is an old drug and thecorrelation in pupil response EXAMPLE I Pilocarpine nitrate 3.0 MineralOil (U.S.P.) 30.0 Tween dl) (a) 2.52 Arlacel-40 (b) 5.48 NaH.Po..H,o0.26 mgwo 0.04s Benzalkonium chloride 0.004 0 EDTA (c) 0.02 1 NaCl 0.26Water to make l00.0

EXAMPLE I! Pilocarpine (free base) l.0 Silicone Oil I00 c.p.s. l0.0 2QPolawax (d) 2.4 NaH,PO, .H,O qs. pH 6 Thimerosal (e) 0.0l NaCl 0.26Water to make 100.0

EXAMPLE [I] Pilocarpine nitrate 4.0 Mineral Oil (U.S.P.) 30.0 Polawax2.l NaH,PO .H,O 0.04 Na,HPO. 0.04 PMA (Phenylmercuric acetate) 0.004Sodium nitrate 0.38 Water to make l00.0

EXAMPLE IV 1: Pilocarpine nitrate 2.0 Corn Oil 50.0 Polawax L8 4 5NaH,PO,.H,O 0.1) Na,HPO 0.46 Thimerosal 0.0I NaCl 0.26

a. Tween 40 is Polyoxyethylene Sorbitan Monopalmitate b. Arlacel 40 isSorbitan Monopalmitate c. Ethylenediaminetetraacetate sodium d. Polawaxis Polyoxyethylene Stearate e. Thirnerosal is SodiumEthylmercurithiosalicylate We claim:

1. An oil-in-water emulsion of a pilocarpine useful in the treatment ofglaucoma containing on a weight basis from about 0.25 to 8 percent of apilocarpine selected from the group consisting of pilocarpinehydrochloride, pilocarpine borate and pilocarpine nitrate, from about 10to percent of a physiologically acceptable oil selected from the groupconsisting of mineral oil, silicone oil and a vegetable oil, anemulsifying amount of a physiologically acceptable emulsifier selectedfrom the group consisting of acacia, gum tragacanth, methyl cellulose,lecithin, cholesterol, polyoxyethylene (40 units) stearate,polyoxyethylene cetyl ether, sorbitan, sorbitan trioleate andpolyoxyethylene (20) sorbitan trioleate and the balance of thecomposition being essentially water.

2. The composition of claim 1 wherein the oil is mineral oil.

3. The composition of claim 1 wherein pilocarpine nitrate is employed.

4. The composition of claim 1 wherein the pH of the aqueous phase oftheemulsion is from 4.5 to 7.

5. The composition of claim 4 wherein the pH is about 6.

2. The composition of claim 1 wherein the oil is mineral oil.
 3. Thecomposition of claim 1 wherein pilocarpine nitrate is employed.
 4. Thecomposition of claim 1 wherein the pH of the aqueous phase of theemulsion is from 4.5 to
 7. 5. The composition of claim 4 wherein the pHis about 6.